The memory of the tumor microenvironment: epigenetic scarring and the hysteretic logic of therapeutic relapse

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Abstract
Tumor progression and therapeutic failure are classically interpreted through the lenses of genetic evolution and ongoing signaling dynamics. However, increasing evidence suggests that tumors are also shaped by durable imprints of prior microenvironmental exposures. These prior exposures can leave persistent epigenetic and structural imprints that progressively stabilize adaptive cellular states, allowing transient responses to become durable regulatory programs. Chronic inflammation, metabolic stress, therapeutic pressure, and extracellular matrix remodeling induce persistent molecular states across cancer cells and stromal compartments, generating history-dependent phenotypes that influence future biological responses. Building on these observations, we propose that these adaptive processes collectively constitute a distributed tumor microenvironment (TME) memory encoded across cancer cells, fibroblasts, immune cells, endothelial cells, and the extracellular matrix (ECM), rather than representing isolated mechanisms of adaptation. We examine how TME memory contributes to therapy resistance, immune dysfunction, cancer-cell dormancy, minimal residual disease, and tumor recurrence, and discuss the molecular mechanisms underlying memory encoding, persistence, and recall. Finally, we discuss the experimental and clinical strategies required to identify memory-rich tumors, develop biomarkers of historical imprinting, and design memory-aware therapeutic interventions. By integrating diverse forms of adaptive persistence within a unified history-dependent framework, TME memory provides a conceptual foundation for investigating tumor evolution, therapeutic resistance, and future precision oncology strategies.

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